Acid-catalyzed reaction of 4-methyl-1,2,4-triazoline-3,5-dione (MeTAD) with substituted benzenes

Article abstract of DOI:10.1016/j.tetlet.2010.12.024

The reaction of 4-methyl-1,2,4-triazoline-3,5-dione (MeTAD) with substituted benzenes under the influence of trifluoroacetic acid catalysis was investigated. Generally, good-to-high yields of 1-arylurazoles resulting from aromatic substitution were obtain

Full text of DOI:10.1016/j.tetlet.2010.12.024

Tetrahedron Letters 52 (2011) 733–735
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Tetrahedron Letters
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Acid-catalyzed reaction of 4-methyl-1,2,4-triazoline-3,5-dione (MeTAD) with
substituted benzenes
⇑
Gary W. Breton
Berry College, Department of Chemistry, PO Box 495016, Mount Berry, GA 30149, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The reaction of 4-methyl-1,2,4-triazoline-3,5-dione (MeTAD) with substituted benzenes under the influ-
ence of trifluoroacetic acid catalysis was investigated. Generally, good-to-high yields of 1-arylurazoles
resulting from aromatic substitution were obtained. Successful reaction required moderately electron-
rich aromatics with proper substitution patterns. The reaction was tolerant of functionality on the aro-
matic ring.
Received 6 October 2010
Revised 3 December 2010
Accepted 6 December 2010
Available online 10 December 2010
Ó 2010 Elsevier Ltd. All rights reserved.
4-Alkyl and 4-aryl-1,2,4-triazoline-3,5-diones (TADs) are potent
azo compound electrophiles. The reactions of TADs with alkenes
and dienes, as well as many other functional groups, have been rig-
orously studied.1 However, only spurious investigations on the
reactions of TADs with substituted benzenes have been re-
ported.2–8 In most cases, TADs react to give 1-arylurazoles, that
is, products expected from an electrophilic substitution reaction
(see Scheme 1).
1-Arylurazoles have potential pharmaceutical applications as
vasodilators, anticonvulsants, and analgesics.9–11 In addition,
oxidation of 1-arylurazoles gives rise to an interesting class of per-
sistent cyclic hydrazyl radicals.12 Given the potential usefulness of
1-arylurazole compounds, the development of novel strategies to-
ward the synthesis of these compounds is warranted. Therefore,
we initiated a systematic study of the reactivity of 4-methyl-
1,2,4-triazoline-3,5-dione (MeTAD, i.e., Scheme 1 where R = Me)
with a series of aromatic compounds under acid-catalyzed condi-
tions. MeTAD was selected as the TAD substrate since its immedi-
ate precursor (the N-methylurazole) is commercially available, and
the characteristic N-methyl signal in the 1H NMR spectrum (gener-
ally ranging from ꢀ2.8 to 3.3 ppm) provides a convenient spectro-
scopic tag for the determination of product distributions in crude
reaction mixtures.
yield), reaction with 1,3-dimethoxybenzene required upwards of
4 days for completion. No reaction was observed at all with less
electron-rich aromatic compounds, such as 3-methylanisole (even
after a month), anisole, or mesitylene.
Trifluoroacetic acid has been used in the past to catalyze reac-
tions of TADs with carbonyl compounds.13 We surmised that TFA
might serve as an effective catalyst for the electrophilic addition
of TADs to substituted benzenes as well. To test this theory, 1 equiv
of trifluoroacetic acid was added to a solution of MeTAD and 1,3,5-
trimethoxybenzene. A 93% yield of urazole 1 was formed within
10 s (Table 1, entry 1). This was a substantial rate enhancement
relative to the corresponding room temperature reaction. Simi-
larly, the addition of an equivalent of TFA to the reaction of MeTAD
and 1,3-dimethoxybenzene resulted in a much faster reaction
(5 min) to afford urazole 2 relative to the uncatalyzed reaction
(see entry 4). The addition of TFA also effectively catalyzed reac-
tions between MeTAD and otherwise thermally unreactive aromat-
ics such as 3-methylanisole (Table 1, entry 5). The TFA-catalyzed
reactions of MeTAD with several other substituted benzenes are
collected in Table 1. Generally, good-to-high yields of 1-aryluraz-
oles were obtained in reasonable reaction times.
Three general trends in reactivity were observed. First, despite
the potential for formation of regioisomers, generally the forma-
tion of a single regioisomer corresponding to substitution of the
Thermal reactions of TADs with electron-rich benzenes, such as
1,3,5-trimethoxybenzene,7 substituted phenols,2,4 and dimethyl
aniline5 to afford the corresponding 1-arylurazoles have been re-
ported in the literature in a series of unconnected publications.
The success of these reactions was dependent on the presence of
sufficiently strong electron-donor groups on the benzene ring.
For example, we observed that while reaction between 1,3,5-tri-
methoxybenzene and MeTAD in CH2Cl2 to afford the 1-arylurazole
(compound 1 in Table 1) required 9 h at room temperature (91%
R
N
R
O
O
R
N
N
N
O
O
H
R
N
N
TAD
1-arylurazole
⇑
Tel.: +1 706 290 2661; fax: +1 706 238 7855.
E-mail address: gbreton@berry.edu
Scheme 1. General reaction of TAD with substituted benzenes to form 1-
arylurazoles.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.024

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G. W. Breton / Tetrahedron Letters 52 (2011) 733–735
Table 1
TFA-catalyzed reactions of MeTAD with substituted aromaticsa,b
Entry
Substrate
Conditions
Product
Yield (%)
93
1
1 equiv, CH2Cl2, rt, <1 min
2
3
1 equiv, CH2Cl2, rt, <1 min
98
99
2 equiv, CHCl3, 62 °C, 7 h
4
1 equiv, CH2Cl2, rt, 5 min
79
5
6
7
8
9
2 equiv, CHCl3, 62 °C, 10 min
2 equiv, CHCl3, 62 °C, 24 h
2 equiv, neat anisole, rt, 2 h
1 equiv, CH2Cl2, rt, 1 h
99
54
53c
96
2 equiv, CH2Cl2, rt, 3 h
92
a
All reactions were conducted according to a standard procedure unless otherwise specified: MeTAD (1 mmol) was added to a stirring solution of the substituted benzene
(1.5 mmol) in 10 mL of solvent. The acid catalyst (equivalents provided in the Table) was added via syringe. If the reaction required heating, the solution was heated at reflux
with a drying tube attached to the reflux condenser. Upon completion of the reaction, the solvent was removed via rotary evaporation. The resulting reaction mixture was
subjected to column chromatography on SiO2 using ethyl acetate as eluent. Characterization information for all new compounds is provided in Supplementary data.
b
UH = N-4-methylurazole with N-1 attached to the aromatic ring and N-2 attached to an H.
A 19% yield of compounds 4 and 5 (in a 60:40 ratio) was also isolated.
c
urazole ring at the position para to the strongest electron-donating
substituent was observed (see, for example, entries 5 and 9). Sec-
ond, less electron-rich aromatic compounds required the addition
of 2 equiv of TFA and heating to reflux (in chloroform) to effect
reaction (entries 3 and 5). The limit of reactivity appeared to be
m-xylene where only a 45% yield of adduct was realized after
24 h. Reaction failed with benzene (used as solvent, 2 equiv of
TFA, 80 °C), even upon prolonged heating (36 h). Finally, reaction
was only feasible with benzenes upon which substitution para
to an electron-donating substituent was possible. Thus, while
1,3-dimethoxybenzene afforded a high yield of 1-arylurazole 2,
1,4-dimethoxybenzene failed to yield any urazole products at all.
Similarly, whereas reaction with mesitylene was successful, reac-
tion with durene (1,2,4,5-tetramethylbenzene) led to complex
reaction mixtures with only trace amounts of the expected 1-
arylurazole being detected.
when the reaction was conducted in neat anisole, a 53% yield of
1-arylurazole 6 was afforded, and only a 19% yield of the disubsti-
tuted urazoles was isolated. To explain the formation of 1,2-diaryl
substituted compounds, we propose that the initially formed 1-
arylurazole 6 is capable of further oxidation, presumably to an
electrophilic species such as 7. Intermediate 7 may then undergo
further reaction with anisole. An intermediate similar to 7 has been
proposed earlier.6 Interestingly, we did not observe the formation
of disubstituted urazoles in any of the other reactions. The scope
and mechanism of this interesting reaction is under current
investigation.
CH3
N
O
O
N
N
Interestingly, attempted reaction with anisole under standard
reaction conditions (1.5 equiv substituted benzene, 2 equiv TFA)
failed to yield the expected 1-arylurazole product. Instead, an iso-
meric mixture of 1,2-diaryl substituted urazoles 4 and 5 (Scheme
2) was isolated in 62% yield (60:40 ratio, respectively). However,
H3CO
7

G. W. Breton / Tetrahedron Letters 52 (2011) 733–735
735
R
N
R
N
R
N
OCH3
O
O
O
O
CH3
N
O
O
N
N
N
N
N
N
OCH3
O
O
+
+
H
CF3CO2H
N
N
H3CO
H3CO
OCH3
H3CO
4
5
6
Scheme 2. TFA-catalyzed reaction of MeTAD with anisole.
In conclusion, TFA-catalyzed reactions of MeTAD with substi-
tuted aromatics afford good-to-excellent yields of 1-arylurazoles
under reasonable reaction conditions. The scope of the reaction is
limited to fairly electron-rich benzenes with an available reaction
site para to an electron-donor group. The reaction is tolerant of
commonly encountered functionalities, such as alkyl, carbome-
thoxy, and acetoxy groups. The mechanism of formation of disub-
stituted urazoles 4 and 5 remains to be further investigated.
References and notes
1. Radl, S. Adv. Heterocycl. Chem. 1997, 67, 119–205.
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Tetrahedron 1996, 52, 2449–2464.
4. Wilson, R. M.; Chantarasiri, N. J. Am. Chem. Soc. 1991, 113, 2301–2302.
5. Mallakpour, S. E.; Butler, G. B. J. Polym. Sci., Part A: Polym. Chem. 1989, 27, 217–
235.
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Chem. Ber. 1988, 121, 1647–1650.
7. Hall, J. H. J. Org. Chem. 1983, 48, 1708–1712.
8. Zander, M. Chem. Ztg 1975, 99, 92–93.
Acknowledgment
9. Ruschig, H.; Schmitt, K.; Ther, L.; Pfaff, W. GB Patent 973359, 1962; Chem. Abstr.
1962, 456301.
10. Mitchell, C. L.; Keasling, H. H.; Gross, E. G. J. Am. Pharm. Assoc. 1959, 48, 122–
126.
This work was supported by the Faculty Development Grant
program of Berry College.
11. Schmitt, K. DE Patent 1135478, 1962; Chem. Abstr. 1963, 8912.
12. Pirkle, W. H.; Gravel, P. L. J. Org. Chem. 1978, 43, 808–815.
13. Wilson, R. M.; Hengge, A. C.; Ataei, A.; Chantarasiri, N. J. Org. Chem. 1990, 55,
193–197.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.12.024.